Gene therapy for bone formation: In vitro and in vivo osteogenic activity of an adenovirus expressing BMP7

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Abstract
Bone morphogenetic proteins (BMPs) are well‐established agents for inducing orthotopic and ectopic bone formation. However, their clinical usefulness as regenerative agents may be limited by a short in vivo half‐life and low specific activity. BMP gene therapy is an alternative route for exploiting the bone‐inductive activity of this class of molecules. To test the feasibility of this approach, we examined the osteogenic activity of AdCMV‐BMP7, an adenovirus containing BMP7 cDNA under control of the CMV promoter that was constructed using Cre/lox recombination (Hardy et al. [1997] J. Virol. 71:1842–1849). Adenovirus vectors were shown to readily infect a wide variety of cell types in vitro including osteoblasts, fibroblasts, and myoblasts. COS7 cells transduced with AdCMV‐BMP7 produced high levels of BMP‐7 (approximately 0.5 μg/106 cells). Furthermore, transduction of C2C12 murine myoblast cells with AdCMVBMP‐7 suppressed the muscle phenotype and induced in vitro osteoblast differentiation. To test its in vivo biological activity, AdCMV‐BMP7 was mixed with a bovine bone‐derived collagen carrier (108 plaque‐forming units virus/site) and was implanted into mouse muscle and dermal pouches. In both cases, an ossicle containing cortical and trabecular bone and a clearly defined marrow cavity formed at the site of virus implantation within 4 weeks. These data demonstrate that AdCMV‐BMP7 transduced cells produce biologically active BMP‐7 both in vitro and in vivo and show that gene therapy by direct viral transduction using a virus/matrix implant may be a viable route for stimulating bone regeneration. J. Cell. Biochem. 78:476–486, 2000.

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